Category: Overlapping Illnesses

Autoantibody-Driven Monocyte Dysfunction in Post-COVID Syndrome with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Post-COVID syndrome (PCS) has emerged as a significant health concern with persisting symptoms. A subset of PCS patients develops severe myalgic encephalomyelitis/chronic fatigue syndrome (pcME/CFS). Dysregulated autoantibodies (AABs) have been implicated in PCS, contributing to immune dysregulation, impairment of autonomous nerve and vascular function. As recently shown in autoimmune diseases, IgG fractions translate disease-specific pathways into various cells. Therefore, we asked whether IgG fractions from PCS patients could be applied in vitro to identify specific cytokine rersponses for PCS patients without (nPCS) and with pcME/CSF.

To assess this, we have stimulated monocyte cell lines with IgG fractions from PCS patients. Our findings reveal distinct patterns of immune regulation by AABs in vascular and immune dysfunction. In contrast to nPCS, pcME/CSF AABs induced enhanced neurotrophic responses, characterized by significant cytokine correlations involving brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF) and LIGHT. AAB-induced cytokine levels correlate with clinical symptoms. Further, this study emphasizes a contribution of AAB in PCS, in mitigating long-term immune dysregulation, and a need for therapies modulating IgG-induced pathways.

Source: Alexander Hackel, Franziska Sotzny, Elise Mennenga, Harald Heidecke, Kai Schulze-Foster,  Kontantinos Fourlakis,  Susanne Lueders, Hanna Grasshoff, Kerstin Rubarth, Frank Konietschke, Tanja Lange, Carmen Scheibenbogen, Reza Akbarzade, Gabriela Riemekasten. Autoantibody-Driven Monocyte Dysfunction in Post-COVID Syndrome with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. medRxiv 2025.01.09.25320264; doi: https://doi.org/10.1101/2025.01.09.25320264 https://www.medrxiv.org/content/10.1101/2025.01.09.25320264v1.full.pdf+html (Full text available as PDF file)

Effect of Immunoadsorption on clinical presentation and immune alterations in COVID-19-induced and/or aggravated ME/CFS

Abstract:

Autoreactive antibodies (AAB) are currently being investigated as causative or aggravating factors during post-COVID. In this study we analyze the effect of immunoadsorption therapy on symptom improvement and the relationship with immunological parameters in post-COVID patients exhibiting symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) induced or aggravated by an SARS-CoV-2 infection. This observational study includes 12 post-COVID patients exhibiting a predominance of ME/CFS symptoms alongside increased concentrations of autonomic nervous system receptors (ANSR) autoantibodies and neurological impairments.

We found that following immunoadsorption therapy, the ANSR autoantibodies were nearly eliminated from the patients’ blood. The removal of IgG antibodies was accompanied by a decrease of pro-inflammatory cytokines including IL4, IL2, IL1β, TNF and IL17A serum levels, and a significant reduction of soluble spike protein. Notably, a strong positive correlation between pro-inflammatory cytokines and ASNR-AABs β1, β2, M3, and M4 was observed in spike protein-positive patients, whereas no such correlation was evident in spike protein-negative patients.

30 days post-immunoadsorption therapy, patients exhibited notable improvement in neuropsychological function and a modest but statistically significant amelioration of hand grip strength was observed. However, neither self-reported symptoms nor scores on ME/CFS questionnaires showed a significant improvement and a rebound of the removed proteins occurring within a month.

Source: Anft M, Wiemers L, Rosiewicz KS, Doevelaar A, Skrzypczyk S, Kurek J, Kaliszczyk S, Seidel M, Stervbo U, Seibert FS, Westhoff TH, Babel N. Effect of Immunoadsorption on clinical presentation and immune alterations in COVID-19-induced and/or aggravated ME/CFS. Mol Ther. 2025 Jan 9:S1525-0016(25)00011-5. doi: 10.1016/j.ymthe.2025.01.007. Epub ahead of print. PMID: 39797400. https://www.cell.com/molecular-therapy-family/molecular-therapy/pdf/S1525-0016(25)00011-5.pdf (Full text) https://pubmed.ncbi.nlm.nih.gov/39797400/ (Abstract)

Incidence and Prevalence of Post-COVID-19 Myalgic Encephalomyelitis: A Report from the Observational RECOVER-Adult Study

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may occur after infection. How often people develop ME/CFS after SARS-CoV-2 infection is unknown.

Objective: To determine the incidence and prevalence of post-COVID-19 ME/CFS among adults enrolled in the Researching COVID to Enhance Recovery (RECOVER-Adult) study.

Design, setting, and participants: RECOVER-Adult is a longitudinal observational cohort study conducted across the U.S. We included participants who had a study visit at least 6 months after infection and had no pre-existing ME/CFS, grouped as (1) acute infected, enrolled within 30 days of infection or enrolled as uninfected who became infected (n=4515); (2) post-acute infected, enrolled greater than 30 days after infection (n=7270); and (3) uninfected (1439).

Measurements: Incidence rate and prevalence of post-COVID-19 ME/CFS based on the 2015 Institute of Medicine ME/CFS clinical diagnostic criteria.

Results: The incidence rate of ME/CFS in participants followed from time of SARS-CoV-2 infection was 2.66 (95% CI 2.63-2.70) per 100 person-years while the rate in matched uninfected participants was 0.93 (95% CI 0.91-10.95) per 100 person-years: a hazard ratio of 4.93 (95% CI 3.62-6.71). The proportion of all RECOVER-Adult participants that met criteria for ME/CFS following SARS-CoV-2 infection was 4.5% (531 of 11,785) compared to 0.6% (9 of 1439) in uninfected participants. Post-exertional malaise was the most common ME/CFS symptom in infected participants (24.0%, 2830 of 11,785). Most participants with post-COVID-19 ME/CFS also met RECOVER criteria for long COVID (88.7%, 471 of 531).

Limitations: The ME/CFS clinical diagnostic criteria uses self-reported symptoms. Symptoms can wax and wane.

Conclusion: ME/CFS is a diagnosable sequela that develops at an increased rate following SARS-CoV-2 infection. RECOVER provides an unprecedented opportunity to study post-COVID-19 ME/CFS.

Source: Vernon SD, Zheng T, Do H, Marconi VC, Jason LA, Singer NG, Natelson BH, Sherif ZA, Bonilla HF, Taylor E, Mullington JM, Ashktorab H, Laiyemo AO, Brim H, Patterson TF, Akintonwa TT, Sekar A, Peluso MJ, Maniar N, Bateman L, Horwitz LI, Hess R; NIH Researching COVID to Enhance Recovery (RECOVER) Consortium. Incidence and Prevalence of Post-COVID-19 Myalgic Encephalomyelitis: A Report from the Observational RECOVER-Adult Study. J Gen Intern Med. 2025 Jan 13. doi: 10.1007/s11606-024-09290-9. Epub ahead of print. PMID: 39804551. https://link.springer.com/article/10.1007/s11606-024-09290-9 (Full text)

Cluster analysis to identify long COVID phenotypes using 129Xe magnetic resonance imaging: a multicentre evaluation

Abstract:

Background: Long COVID impacts ∼10% of people diagnosed with coronavirus disease 2019 (COVID-19), yet the pathophysiology driving ongoing symptoms is poorly understood. We hypothesised that 129Xe magnetic resonance imaging (MRI) could identify unique pulmonary phenotypic subgroups of long COVID. Therefore, we evaluated ventilation and gas exchange measurements with cluster analysis to generate imaging-based phenotypes.

Methods: COVID-negative controls and participants who previously tested positive for COVID-19 underwent 129Xe MRI ∼14 months post-acute infection across three centres. Long COVID was defined as persistent dyspnoea, chest tightness, cough, fatigue, nausea and/or loss of taste/smell at MRI; participants reporting no symptoms were considered fully recovered. 129Xe MRI ventilation defect percent (VDP) and membrane-to-gas (Mem/Gas), red blood cell-to-membrane (RBC/Mem) and red blood cell-to-gas (RBC/Gas) ratios were used in k-means clustering for long COVID, and measurements were compared using ANOVA with post-hoc Bonferroni correction.

Results: We evaluated 135 participants across three centres: 28 COVID-negative (mean±sd age 40±16 years), 34 fully recovered (42±14 years) and 73 long COVID (49±13 years). RBC/Mem (p=0.03) and forced expiratory volume in 1 s (FEV1) (p=0.04) were different between long COVID and COVID-negative; FEV1 and all other pulmonary function tests (PFTs) were within normal ranges. Four unique long COVID clusters were identified compared with recovered and COVID-negative. Cluster 1 was the youngest with normal MRI and mild gas trapping; Cluster 2 was the oldest, characterised by reduced RBC/Mem but normal PFTs; Cluster 3 had mildly increased Mem/Gas with normal PFTs; and Cluster 4 had markedly increased Mem/Gas with concomitant reduction in RBC/Mem and restrictive PFT pattern.

Conclusions: We identified four 129Xe MRI long COVID phenotypes with distinct characteristics. 129Xe MRI can dissect pathophysiological heterogeneity of long COVID to enable personalised patient care.

Source: Eddy RL, Mummy D, Zhang S, Dai H, Bechtel A, Schmidt A, Frizzell B, Gerayeli FV, Leipsic JA, Leung JM, Driehuys B, Que LG, Castro M, Sin DD, Niedbalski PJ. Cluster analysis to identify long COVID phenotypes using 129Xe magnetic resonance imaging: a multicentre evaluation. Eur Respir J. 2024 Mar 28;63(3):2302301. doi: 10.1183/13993003.02301-2023. PMID: 38331459; PMCID: PMC10973687. https://pmc.ncbi.nlm.nih.gov/articles/PMC10973687/ (Full text)

Relationship between major depressive disorder and myalgic encephalomyelitis/chronic fatigue syndrome: a two-sample mendelian randomization study analysis

Abstract:

Major depressive disorder (MDD) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) frequently occur together; yet their causal relationship remains unclear. To investigate the potential genetic causal link between these conditions, we conducted a two-sample Mendelian randomization (MR) analysis.

Summary data from Genome-Wide Association Studies (GWAS) for MDD were sourced from the UK Biobank and the Psychiatric Genomics Consortium, while GWAS data for ME/CFS were retrieved from the UK Biobank. Inverse-variance weighting (IVW), the MR-Egger method, and weighted median, simple and weighted modes were used to perform the MR analysis. In addition, Cochrane’s Q-test was used to detect heterogeneity among the MR results. Horizontal pleiotropy was detected using the MR-Egger intercept and the MR pleiotropy residual sum and outlier (MR-PRESSO) tests. Leave-one-out analysis was performed to investigate the sensitivity of the association between MDD and ME/CFS.

The results of the MR analysis revealed no causal relationship between MDD and ME/CFS. The pleiotropy test revealed that causality bias was improbable, and no evidence of heterogeneity was found among the genetic variants. Finally, the leave-one-out test confirmed the stability and robustness of our findings.

Source: Song, W., Hou, X., Wu, M. et al. Relationship between major depressive disorder and myalgic encephalomyelitis/chronic fatigue syndrome: a two-sample mendelian randomization study analysis. Sci Rep 15, 1155 (2025). https://doi.org/10.1038/s41598-025-85217-6 https://www.nature.com/articles/s41598-025-85217-6 (Full text)

Efficacy of repeated immunoadsorption in patients with post-COVID myalgic encephalomyelitis/chronic fatigue syndrome and elevated β2-adrenergic receptor autoantibodies: a prospective cohort study

Abstract:

Background: Since the pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become the leading trigger for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Evidence indicates that autoimmunity plays an important pathophysiological role. We aimed to evaluate the effectiveness of IA treatment in post-COVID ME/CFS patients.

Methods: This pre-post study included 20 post-coronavirus disease 2019 (COVID) ME/CFS patients found to have elevated β2 adrenergic autoantibodies (β2 AR-AB) between October 2022 and October 2023. Patients, with a median disease duration of 22 months (IQR: 15-31), were treated with five immunoadsorption sessions at Charité – Universitätsmedizin Berlin, Germany. Seven were male and 13 female, with a median age of 40 years (IQR: 36-51). The primary end point was the change in the Short Form (36) Health Survey physical functioning domain (SF36 PF) from baseline to four weeks post immunoadsorption. Key symptoms were assessed via questionnaires over six months. Handgrip strength and EndoPAT® measurements were used to evaluate muscle fatigue and vascular dysfunction. Seven patients who worsened after an initial response received a second cycle.

Findings: The treatment was generally well tolerated, reducing total immunoglobulin G by 79% (CI: 73-84%) and β2 AR-AB by 77% (CI: 58-95%). Patients demonstrated a mean increase in the SF36 PF of 17.75 points (CI: 13.41-26.16), with the greatest improvement occurring between months two and three, and significant gains maintained through month six. 14/20 (70%) patients were categorized as responders with an increase in the SF36 PF of ≥ ten points. Further lasting improvements were reported in fatigue, post-exertional malaise, pain, cognitive, autonomic, and immunological symptoms. Female patients had increased repeat handgrip strength at month six.

Interpretation: Immunoadsorption may improve symptoms in post-COVID ME/CFS patients. The beneficial effects of IgG depletion suggest a significant role for autoantibodies and disturbed B-cell function in the condition’s pathophysiology.

Funding: Funded by The Federal Ministry of Education and Research and the Weidenhammer Zöbele Research Foundation.

Source: Stein E, Heindrich C, Wittke K, Kedor C, Rust R, Freitag H, Sotzny F, Krüger A, Tölle M, Grabowski P, Scheibenbogen C, Kim L. Efficacy of repeated immunoadsorption in patients with post-COVID myalgic encephalomyelitis/chronic fatigue syndrome and elevated β2-adrenergic receptor autoantibodies: a prospective cohort study. Lancet Reg Health Eur. 2024 Dec 12;49:101161. doi: 10.1016/j.lanepe.2024.101161. PMID: 39759581; PMCID: PMC11699797. https://pmc.ncbi.nlm.nih.gov/articles/PMC11699797/ (Full text)

More than “Brain Fog”: Cognitive Dysfunction and the Role of Occupational Therapy in Long COVID

Abstract:

Long COVID is a disabling condition which affects occupational performance and quality of life. It interferes with activities of daily living, work, and many meaningful life roles. Cognitive dysfunction is a frequently reported symptom, yet it is commonly overlooked. It is important that cognitive activity is considered when working with people with long COVID, particularly when identifying triggers of post exertional symptom exacerbation. There are many potential mechanisms that could be driving cognitive dysfunction in long COVID including neuroinflammation, viral persistence, vascular damage, and orthostatic intolerance. It is important to consider these to help guide intervention.

The purpose of this clinical perspective is to highlight the debilitating impact of cognitive dysfunction in those with long COVID and share the key role of occupational therapists in this area. Cognitive dysfunction may be missed on standardized assessments as they may not be sensitive enough due to the episodic nature of symptoms. Occupational therapists can play a key role in this area as they are experts in assessing occupational performance and in providing safe cognitive assessment and rehabilitation.

Source: Skiffington, Helen OT, BSc Hons1,2; Breen, Ciara MSc, HCM3,4,5. More than “Brain Fog”: Cognitive Dysfunction and the Role of Occupational Therapy in Long COVID. Cardiopulmonary Physical Therapy Journal 36(1):p 39-49, January 2025. | DOI: 10.1097/CPT.0000000000000274 https://journals.lww.com/cptj/fulltext/2025/01000/more_than__brain_fog___cognitive_dysfunction_and.7.aspx (Full text)

A Single-Center Pilot Study of Therapeutic Apheresis in Patients with Severe Post-COVID Syndrome

Abstract:

After the COVID-19 pandemic, many patients have reported chronic fatigue and severe post-exertional malaise, with symptoms similar to those of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The accumulation of agonistic receptor autoantibodies targeting beta-adrenergic (β1 and β2) and muscarinic (M3 and M4) neurotransmitter receptors may play a crucial role in the pathomechanism of both ME/CFS and post-COVID conditions.

Therapeutic apheresis has been suggested as an effective treatment option for alleviating and mitigating symptoms in this desperate group of patients. In this single-center pilot study, we analyzed autoantibodies in a cohort of 20 post-COVID patients before and after therapeutic apheresis. Apheresis resulted in a decline of β1 or β2 adrenergic receptor antibodies in all patients. Additionally, the majority of patients experienced a concurrent reduction in symptoms such as fatigue, physical activity restrictions, myalgia, post-exertional malaise, and concentration disorders.

This study clearly demonstrates an association between autoantibodies and the clinical improvement of post-COVID patients. Even if future sham-controlled trials do not show a positive outcome, extracorporeal apheresis may still be valuable for this patient group by temporarily improving microperfusion and symptoms. Success in restoring patients to work and normal life, as observed in many individuals after therapeutic apheresis, should be recognized. Therefore, we believe that extracorporeal therapeutic apheresis, as part of a multimodal treatment, should be considered an early intervention for postinfectious syndromes in selected patients.

Source: Korth J, Steenblock C, Walther R, Barbir M, Husung M, Velthof A. A Single-Center Pilot Study of Therapeutic Apheresis in Patients with Severe Post-COVID Syndrome. Horm Metab Res. 2024 Dec;56(12):869-874. doi: 10.1055/a-2445-8593. Epub 2024 Dec 9. PMID: 39653042. https://pubmed.ncbi.nlm.nih.gov/39653042/

Phase-dependent trends in the prevalence of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) related to long COVID: A criteria-based retrospective study in Japan

Abstract:

Background: The characteristics of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) related to COVID-19 have remained uncertain. To elucidate the clinical trend of ME/CFS induced by long COVID, we examined data for patients who visited our outpatient clinic established in a university hospital during the period from Feb 2021 to July 2023.

Methods: Long COVID patients were classified into two groups, an ME/CFS group and a non-ME/CFS group, based on three diagnostic criteria.

Results: The prevalence of ME/CFS in the long COVID patients was 8.4% (62 of 739 cases; female: 51.6%) and factors related to ME/CFS were severe illness, smoking and alcohol drinking habits, and fewer vaccinations. The frequency of ME/CFS decreased from 23.9% in the Preceding period to 13.7% in the Delta-dominant period and to 3.3% in the Omicron-dominant period. Fatigue and headache were commonly frequent complaints in the ME/CFS group, and the frequency of poor concentration in the ME/CFS group was higher in the Omicron period. Serum ferritin levels were significantly higher in female patients in the ME/CFS group infected in the Preceding period. In the ME/CFS group, the proportion of patients complaining of brain fog significantly increased from 22.2% in the Preceding period to 47.9% in the Delta period and to 81.3% in the Omicron period. The percentage of patients who had received vaccination was lower in the ME/CFS group than the non-ME/CFS group over the study period, whereas there were no differences in the vaccination rate between the groups in each period.

Conclusion: The proportion of long COVID patients who developed ME/CFS strictly diagnosed by three criteria was lower among patients infected in the Omicron phase than among patients infected in the other phases, while the proportion of patients with brain fog inversely increased. Attention should be paid to the variant-dependent trends of ME/CFS triggered by long COVID (300 words).

Source: Morita S, Tokumasu K, Otsuka Y, Honda H, Nakano Y, Sunada N, Sakurada Y, Matsuda Y, Soejima Y, Ueda K, Otsuka F. Phase-dependent trends in the prevalence of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) related to long COVID: A criteria-based retrospective study in Japan. PLoS One. 2024 Dec 9;19(12):e0315385. doi: 10.1371/journal.pone.0315385. PMID: 39652555; PMCID: PMC11627433. https://pmc.ncbi.nlm.nih.gov/articles/PMC11627433/ (Full text)

Chronic inflammatory response syndrome: a review of the evidence of clinical efficacy of treatment

Abstract:

Chronic Inflammatory Response Syndrome (CIRS) is an acquired medical condition characterized by innate immune dysregulation following respiratory exposure to water-damaged buildings (WDB). This chronic syndrome involves a range of symptoms that simultaneously affecting multiple organ systems. The purpose of this literature review was to search the published literature for successful treatments for chronic inflammatory response syndrome, an under-recognized, underdiagnosed, multisymptom multisystem illness that can affect up to 25% of the population, thus representing a silent epidemic.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a common misdiagnosis for CIRS, is an entity that has broader awareness within the medical community despite the absence of a defined etiology, biomarkers or a treatment protocol that reverses the underlying conditions. Therefore, the search also included treatments for ME/CFS and sick building syndrome (SBS). Thirteen articles referenced treatment for CIRS, and 22 articles referenced treatment for CFS.

The only treatment with documented clinical efficacy was the Shoemaker Protocol, which was described in 11 of the 13 articles. This treatment protocol exhibits superior outcomes compared with the treatment protocols for ME/CFS.

Source: Dooley M, Vukelic A, Jim L. Chronic inflammatory response syndrome: a review of the evidence of clinical efficacy of treatment. Ann Med Surg (Lond). 2024 Nov 8;86(12):7248-7254. doi: 10.1097/MS9.0000000000002718. PMID: 39649915; PMCID: PMC11623837. https://pmc.ncbi.nlm.nih.gov/articles/PMC11623837/ (Full text)